8-OH-DPAT abolishes the pulmonary C-fiber-mediated apneic response to fentanyl largely via acting on 5HT_1Areceptors in the nucleus tractus solitarius

Abstract

Intravenous bolus injection of morphine causes a vagal-mediated brief apnea (∼3 s), while continuous injection, via action upon central μ-opioid receptor (MOR), arrests ventilation (>20 s) that is eliminated by stimulating central 5-hydroxytryptamine 1A receptors (5HT(1A)Rs). Bronchopulmonary C-fibers (PCFs) are essential for triggering a brief apnea, and their afferents terminate at the caudomedial region of the nucleus tractus solitarius (mNTS) that densely expresses 5HT(1A)Rs. Thus we asked whether the vagal-mediated apneic response to MOR agonists was PCF dependent, and if so, whether this apnea was abolished by systemic administration of 8-hydroxy-2-(di-n-propylamino)tetral (8-OH-DPAT) largely through action upon mNTS 5HT(1A)Rs. Right atrial bolus injection of fentanyl (5.0 μg/kg, a MOR agonist) was performed in the anesthetized and spontaneously breathing rats before and after: 1) selective blockade of PCFs' conduction and subsequent bivagotomy; 2) intravenous administration of 5HT(1A)R agonist 8-OH-DPAT; 3) intra-mNTS injection of 8-OH-DPAT; and 4) intra-mNTS injection of 5HT(1A)R antagonist WAY-100635 followed by 8-OH-DPAT (iv). We found the following: First, fentanyl evoked an immediate apnea (2.5 ± 0.4 s, ∼6-fold longer than the baseline expiratory duration, T(E)), which was abolished by either blocking PCFs' conduction or bivagotomy. Second, this apnea was prevented by systemic 8-OH-DPAT challenge. Third, intra-mNTS injection of 8-OH-DPAT greatly attenuated the apnea by 64%. Finally, intra-mNTS microinjection of WAY-100635 significantly attenuated (58%) the apneic blockade by 8-OH-DPAT (iv). We conclude that the vagal-mediated apneic response to MOR activation depends on PCFs, which is fully antagonized by systemic 8-OH-DPAT challenge largely via acting on mNTS 5HT(1A)Rs.

Isoflurane inhibits bronchopulmonary C-fiber-mediated apneic response to phenylbiguanide by depressing 5-HT3 receptor function in anesthetized rats

“…The excitatory effect on PCFs can exaggerate PCF-mediated respiratory response to PBG, which is shown in a previous study [25] where fentanyl, another PCF stimulant [27], facilitated PBG-induced tachypnea. It is believed that the excitatory effect on PCFs by ISO should be overwhelmed by its inhibitory effect on 5-HT 3 receptors, resulting in a shortened (rather than prolonged) PBG-induced apnea by ISO.…”

Neuronal mechanisms underlying opioid-induced respiratory depression: our current understanding

“…Vagotomy or vagal cooling sufficient to block c-fibers eliminated this effect (287). Since that time, a wealth of evidence has emerged that strongly supports the concept that peripherally administered opioid drugs, especially m-opioid agonists, can induce apnea and rapid shallow breathing (288)(289)(290)(291)(292)(293)(294)(295)(296).…”

Perivagal antagonist treatment in rats selectively blocks the reflex and afferent responses of vagal lung C fibers to intravenous agonists

“…In these circumstances, selective blockade of these pharmacological receptors is usually achieved by systemic administration of receptor antagonists (8,11,15,19,33,35,43,60). One obvious shortcoming of such systemic treatment is that antagonists may also block pharmacological receptors located at other peripheral sites (i.e., airway smooth muscles) (36,38,42) or at central sites (54,58,62), both of which might interfere with the elicitation of C-fiber-mediated airway responses. In other investigations (2,55), aerosolized receptor antagonists are delivered into the airways as an alternate method that improves, but does not eliminate, off-target effects compared with systemic administration.…”